tbuckley/cabot-search huggingface dataset:
Oxonium ion scanning mass spectrometry for large-scale plasma glycoproteomics
Authors: Matthew E. H. White, Ludwig R. Sinn, D. Marc Jones, Joost de Folter, Simran Kaur Aulakh, Ziyue Wang, Helen R. Flynn, Lynn Krüger, Pinkus Tober-Lau, Vadim Demichev, Florian Kurth, Michael Mülleder, Véronique Blanchard, Christoph B. Messner, Markus Ralser
Journal: Nature Biomedical Engineering (2023)

Abstract Protein glycosylation, a complex and heterogeneous post-translational modification that is frequently dysregulated in disease, has been difficult to analyse at scale. Here we report a data-independent acquisition technique for the large-scale mass-spectrometric quantification of glycopeptides in plasma samples. The technique, which we named ‘OxoScan-MS’, identifies oxonium ions as glycopeptide fragments and exploits a sliding-quadrupole dimension to generate comprehensive and untargeted oxonium ion maps of precursor masses assigned to fragment ions from non-enriched plasma samples. By applying OxoScan-MS to quantify 1,002 glycopeptide features in the plasma glycoproteomes from patients with COVID-19 and healthy controls, we found that severe COVID-19 induces differential glycosylation in IgA, haptoglobin, transferrin and other disease-relevant plasma glycoproteins. OxoScan-MS may allow for the quantitative mapping of glycoproteomes at the scale of hundreds to thousands of samples.
Cell-free, high-density lipoprotein–specific phospholipid efflux assay predicts incident cardiovascular disease
Authors: Masaki Sato, Edward B. Neufeld, Martin P. Playford, Yu Lei, Alexander V. Sorokin, Angel M. Aponte, Lita A. Freeman, Scott M. Gordon, Amit K. Dey, Kianoush Jeiran, Masato Hamasaki, Maureen L. Sampson, Robert D. Shamburek, Jingrong Tang, Marcus Y. Chen, Kazuhiko Kotani, Josephine L.C. Anderson, Robin P.F. Dullaart, Nehal N. Mehta, Uwe J.F. Tietge, Alan T. Remaley
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDCellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL-cholesterol (HDL-C) but is not suitable as a routine clinical assay.METHODSWe developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels.RESULTSReceiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P < 0.001).CONCLUSIONHDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery.TRIAL REGISTRATIONClinicalTrials.gov NCT01621594.FUNDINGNHLBI Intramural Research Program, NIH (HL006095-06).
The association between allergic rhinitis and the risk of coronavirus disease 2019 (<scp>COVID</scp>‐19): A national survey in China
Authors: Xiaozhe Yang, Jinming Zhao, Yutong Sima, Yan Zhao, Jing Zhang, Xiangdong Wang, Luo Zhang
Journal: Allergy (2023)

The data that support the findings of this study are available from the corresponding author upon reasonable request. Appendix S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
A Road Map for Peer Review of Real-World Evidence Studies on Safety and Effectiveness of Treatments
Authors: Almut G. Winterstein, Vera Ehrenstein, Jeffrey S. Brown, Til Stürmer, Meredith Y. Smith
Journal: Diabetes Care (2023)

The growing acceptance of real-world evidence (RWE) in clinical and regulatory decision-making, coupled with increasing availability of health care data and advances in automated analytic approaches, has contributed to a marked expansion of RWE studies of diabetes and other diseases. However, a recent spate of high-profile retractions highlights the need for improvements in the conduct of RWE research as well as in the associated peer review and editorial processes. We review best pharmacoepidemiologic practices and common pitfalls regarding design, measurement, analysis, data validity, appropriateness, and generalizability of RWE studies. To enhance RWE study assessments, we propose that journal editors require 1) study authors to complete RECORD-PE, a reporting guideline for pharmacoepidemiological studies on routinely collected data, 2) availability of predetermined study protocols and analysis plans, 3) inclusion of pharmacoepidemiologists on the peer review team, and 4) provision of detail on data provenance, characterization, and custodianship to facilitate assessment of the data source. We recognize that none of these steps guarantees a high-quality research study. Collectively, however, they permit an informed assessment of whether the study was adequately designed and conducted and whether the data source used was fit for purpose.
Novel Genomic Risk Stratification Model for Primary Gastrointestinal Stromal Tumors (GIST) in the Adjuvant Therapy Era
Authors: Josephine K. Dermawan, Ciara Kelly, Zhidong Gao, Shaleigh Smith, Bhumika Jadeja, Samuel Singer, William D. Tap, Ping Chi, Cristina R. Antonescu
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Traditional risk stratification schemes in gastrointestinal stromal tumors (GIST) were defined in the pre-imatinib era and rely solely on clinicopathologic metrics. We hypothesize that genomic-based risk stratification is prognostically relevant in the current era of tyrosine kinase inhibitor (TKI) therapeutics. Experimental Design: Comprehensive mutational and copy-number profiling using MSK-IMPACT was performed. We integrated clinicopathologic and genomic parameters and utilized an elastic-net penalized Cox proportional hazards machine learning model for outcome risk stratification. Results: A 3-tier genomic risk stratification model for recurrence-free survival (RFS) in 152 primary localized gastric and 80 small bowel GISTs was proposed. Gastric GISTs were classified as high risk if chr1p deletion or SDHB loss was present, and intermediate risk if chr14q deletion was present or KIT exon 11 mutation was absent. Small bowel GISTs were classified as high risk if MAX/MGA/MYC, CDKN2A, or RB1 alterations were present, and intermediate risk if chr1p deletion or chr5q amplification was present. Compared with conventional risk stratification, genomic risk stratification both upgrades and downgrades, suggesting that conventional risk stratification may underestimate or overtreat some high-risk and low-risk patients, respectively. Longitudinal sequencing detected most KIT-independent genomic alterations at baseline. Subanalysis in 26 SDH-deficient GISTs revealed that presence of TP53 mutations or chr1q amplifications portends worse RFS and disease-free survival. Conclusions: We developed a novel, next-generation genomic risk stratification model for primary gastric and small bowel GISTs, complementing traditional clinicopathologic models. Future independent validation of our model in external cohorts is essential.
Culture, ethnicity, and socio‐economic status as determinants of the management of patients with advanced heart failure who need palliative care: A clinical consensus statement from the Heart Failure Association (<scp>HFA</scp>) of the <scp>ESC</scp>, the <scp>ESC</scp> Patient Forum, and the European Association of Palliative Care
Authors: Loreena Hill, Resham Baruah, James M. Beattie, Vasiliki Bistola, Teresa Castiello, Jelena Celutkienė, Giuseppe Di Stolfo, Tal Prager Geller, Ekaterini Lambrinou, Richard Mindham, Sonja McIlfatrick, Anna Strömberg, Tiny Jaarsma
Journal: European Journal of Heart Failure (2023)

The delivery of effective healthcare entails the configuration and resourcing of health economies to address the burden of disease, including acute and chronic heart failure, that affects local populations. Increasing migration is leading to more multicultural and ethnically diverse societies worldwide, with migration research suggesting that minority populations are often subject to discrimination, socio-economic disadvantage, and inequity of access to optimal clinical support. Within these contexts, the provision of person-centred care requires medical and nursing staff to be aware of and become adept in navigating the nuances of cultural diversity, and how that can impact some individuals and families entrusted to their care. This paper will examine current evidence, provide practical guidance, and signpost professionals on developing cultural competence within the setting of patients with advanced heart failure who may benefit from palliative care.
Intravitreal CendR peptides target laser-induced choroidal neovascularization sites in mice
Authors: Jooseppi Puranen, Sonja Korhonen, Maarja Haugas, Prakash Lingasamy, Tambet Teesalu, Astrid Subrizi, Arto Urtti, Marika Ruponen, Mika Reinisalo
Journal: Journal of Controlled Release (2023)

Choroidal neovascularization (CNV) is a common ocular pathology that may be associated in a variety of eye diseases. Although intravitreal injection treatment of anti-vascular endothelial growth factor (anti-VEGF) drugs shows significant clinical benefits in CNV treatment, the limitations of the current therapy need to be addressed. The aim of our study was to investigate the potential utility of three C-end Rule (CendR) peptides (RPARPAR, PL3, iRGD) for CNV targeting and to evaluate the efficacy of peptides for treating experimental CNV in mice. We observed that the CendR peptides localize to the CNV lesion sites after intravitreal injection and were mainly found in the outer nuclear cell layer (ONL) of the mouse retina. Interestingly, experimental therapy with tenascin-C (TNC-C) and neuropilin-1 (NRP-1)-targeting PL3 peptide, reduced angiogenesis and decreased vascular leakage. The results suggest that PL3 and potentially other CendR peptides could serve as affinity targeting ligands and therapeutics for ocular diseases that involve pathological CNV.
Association of Labor Epidural Analgesia, Oxytocin Exposure, and Risk of Autism Spectrum Disorders in Children
Authors: Chunyuan Qiu, Sarah A. Carter, Jane C. Lin, Jiaxiao M. Shi, Ting Chow, Vimal N. Desai, Vu T. Nguyen, Joseph Spitzer, R. Klara Feldman, Anny H. Xiang
Journal: JAMA Network Open (2023)

Importance Maternal labor epidural analgesia (LEA) and oxytocin use for labor and delivery have been reported to be associated with child autism spectrum disorders (ASD). However, it remains unclear whether these 2 common medications used during labor and delivery have synergistic associations with ASD risk in children. Objective To assess the independent associations of LEA and oxytocin during labor and delivery with ASD, as well as outcome modification associated with the concurrent use of both interventions. Design, Setting, and Participants Data for this cohort study included 205 994 singleton births with vaginal deliveries in a single integrated health care system in Southern California from calendar years 2008 to 2017. Children were followed up to December 31, 2021. Data on use of LEA and oxytocin, covariates, and ASD outcome in children were obtained from electronic medical records. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) adjusting for covariates. Exposures Labor epidural analgesia and/or oxytocin use during labor and delivery. Main Outcomes and Measures A child’s clinical diagnosis of ASD during follow-up and at age of diagnosis. Results Among the cohort, 153 880 children (74.7%) were exposed to maternal LEA and 117 808 children (57.2%) were exposed to oxytocin during labor and delivery. The population of children was approximately half boys and half girls. The median (IQR) age of the mothers was 30.8 (26.8-34.5) years for those not exposed to LEA, 30.0 (25.9-33.8) years for those exposed to LEA, 30.4 (26.5-34.1) years for those unexposed to oxytocin, and 30.0 (25.9-33.9) years for those exposed to oxytocin during labor and delivery. A total of 5146 children (2.5%) had ASD diagnosed during follow-up. Oxytocin exposure was higher among LEA-exposed (67.7%) than -unexposed (26.1%) children. The ASD risk associated with LEA was independent of oxytocin exposure (HR, 1.28; 95% CI, 1.18-1.38); however, the ASD risk associated with oxytocin was not significant after adjusting for LEA exposure (HR, 1.05; 95% CI, 0.99-1.12). A significant interaction of LEA and oxytocin on child ASD risk was found ( P = .02 for interaction). Compared with no exposure, HRs were 1.20 (95% CI, 1.09-1.32) for LEA alone, 1.30 (95% CI, 1.20-1.42) for both LEA and oxytocin, and 0.90 (95% CI, 0.78-1.04) for oxytocin alone. Conclusions and Relevance The findings of this cohort study suggest an association between maternal LEA and ASD risk in children, and the risk appeared to be further increased if oxytocin was also administered. Oxytocin exposure without LEA exposure was not associated with ASD risk in children. These findings must be interpreted with caution. Further studies are needed to replicate or refute the study results and examine biological plausibility.
Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity
Authors: Muhammad Shuaib, Sabir Adroub, Tobias Mourier, Sara Mfarrej, Huoming Zhang, Luke Esau, Afrah Alsomali, Fadwa S Alofi, Adeel Nazir Ahmad, Abbas Shamsan, Asim Khogeer, Anwar M. Hashem, Naif A. M. Almontashiri, Sharif Hala, Arnab Pain
Journal: Genome Medicine (2023)

The excessive inflammatory responses provoked by SARS-CoV-2 infection are critical factors affecting the severity and mortality of COVID-19. Previous work found that two adjacent co-occurring mutations R203K and G204R (KR) on the nucleocapsid (N) protein correlate with increased disease severity in COVID-19 patients. However, links with the host immune response remain unclear.Here, we grouped nasopharyngeal swab samples of COVID-19 patients into two cohorts based on the presence and absence of SARS-CoV-2 nucleocapsid KR mutations. We performed nasopharyngeal transcriptome analysis of age, gender, and ethnicity-matched COVID-19 patients infected with either SARS-CoV-2 with KR mutations in the N protein (KR patients n = 39) or with the wild-type N protein (RG patients n = 39) and compared to healthy controls (n = 34). The impact of KR mutation on immune response was further characterized experimentally by transcriptomic and proteomic profiling of virus-like-particle (VLP) incubated cells.We observed markedly elevated expression of proinflammatory cytokines, chemokines, and interferon-stimulated (ISGs) genes in the KR patients compared to RG patients. Using nasopharyngeal transcriptome data, we found significantly higher levels of neutrophils and neutrophil-to-lymphocyte (NLR) ratio in KR patients than in the RG patients. Furthermore, transcriptomic and proteomic profiling of VLP incubated cells confirmed a similar hyper-inflammatory response mediated by the KR variant.Our data demonstrate an unforeseen connection between nucleocapsid KR mutations and augmented inflammatory immune response in severe COVID-19 patients. These findings provide insights into how mutations in SARS-CoV-2 modulate host immune output and pathogenesis and may contribute to more efficient therapeutics and vaccine development.
Porto-pulmonary hypertension in patients considered for liver transplantation: a cohort study
Authors: Ilaria Curro, Declan Lewis, Tasneem Pirani, Robert Loveridge, Varuna Aluvihare, Krishna Menon, William Bernal, Christopher Willars, Mark Mcphail, Julia Wendon, Georg Auzinger, Sameer Patel
Journal: Journal of Hepatology (2023)
The efficacy of direct-acting antivirals for chronic hepatitis C in patients with the active oncological disease
Authors: Maria Dąbrowska, Jerzy Jaroszewicz, Marek Sitko, Janocha-Litwin Justyna, Dorota Zarębska-Michaluk, Ewa Janczewska, Beata Lorenc, Magdalena Tudrujek, Anna Parfieniuk-Kowerda, Jakub Klapaczynski, Hanna Berak, Łukasz Socha, Beata Dobracka, Dorota Dybowska, Wlodzimierz Mazur, Robert Flisiak
Journal: Journal of Hepatology (2023)
Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer
Authors: Xiaoling Li, Yunguan Wang, Su Deng, Guanghui Zhu, Choushi Wang, Nickolas A. Johnson, Zeda Zhang, Carla Rodriguez Tirado, Yaru Xu, Lauren A. Metang, Julisa Gonzalez, Atreyi Mukherji, Jianfeng Ye, Yuqiu Yang, Wei Peng, Yitao Tang, Mia Hofstad, Zhiqun Xie, Heewon Yoon, Liping Chen, Xihui Liu, Sujun Chen, Hong Zhu, Douglas Strand, Han Liang, Ganesh Raj, Housheng Hansen He, Joshua T. Mendell, Bo Li, Tao Wang, Ping Mu
Journal: Cancer Cell (2023)

Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, EP300. Functional screening identifies eight crucial drivers for androgen receptor (AR)-targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.
Mechanical confinement promotes heat resistance of hepatocellular carcinoma via SP1/IL4I1/AHR axis
Authors: Guo-pei Zhang, Zong-lin Xie, Juan Jiang, Yu-tong Zhao, Kai Lei, Zhi-long Lin, Shu-ling Chen, Tian-hong Su, Li Tan, Sui Peng, Ji Wang, Chun Liu, Ming Kuang
Journal: Cell Reports Medicine (2023)

Mechanical stress can modulate the fate of cells in both physiological and extreme conditions. Recurrence of tumors after thermal ablation, a radical therapy for many cancers, indicates that some tumor cells can endure temperatures far beyond physiological ones. This unusual heat resistance with unknown mechanisms remains a key obstacle to fully realizing the clinical potential of thermal ablation. By developing a 3D bioprinting-based thermal ablation system, we demonstrate that hepatocellular carcinoma (HCC) cells in this 3D model exhibit enhanced heat resistance as compared with cells on plates. Mechanistically, the activation of transcription factor SP1 under mechanical confinement enhances the transcription of Interleukin-4-Induced-1, which catalyzes tryptophan metabolites to activate the aryl hydrocarbon receptor (AHR), leading to heat resistance. Encouragingly, the AHR inhibitor prevents HCC recurrence after thermal ablation. These findings reveal a previously unknown role of mechanical confinement in heat resistance and provide a rationale for AHR inhibitors as neoadjuvant therapy.
In This Issue of <i>Diabetes Care</i>
Authors: Max Bingham
Journal: Diabetes Care (2023)

HbA1c increased over 2-9 years in five categories of baseline HbA1c (<5.7% to >8.0%).TODAY Study Group.Effect of early glycemic control in youth-onset type 2 diabetes on longer-term glycemic control and β-cell function: results from the TODAY study.
TRAF6 regulates autophagy and apoptosis of melanoma cells through c‐Jun/ATG16L2 signaling pathway
Authors: Yeye Guo, Xu Zhang, Jie Li, Zhe Zhou, Susi Zhu, Waner Liu, Juan Su, Xiang Chen, Cong Peng
Journal: MedComm (2023)

Abstract Autophagy and apoptosis are essential processes that participate in cell death and maintain cellular homeostasis. Dysregulation of these biological processes results in the development of diseases, including cancers. Therefore, targeting the interaction between apoptosis and autophagy offers a potential strategy for cancer therapy. Melanoma is the most lethal skin cancer. We previously found that tumor necrosis factor receptor‐associated factor 6 (TRAF6) is overexpressed in melanoma and benefits the malignant phenotype of melanoma cells. Additionally, TRAF6 promotes the activation of cancer‐associated fibroblasts in melanoma. However, the role of TRAF6 in autophagy and apoptosis remains unclear. In this study, we found that knockdown of TRAF6 induced both apoptosis and autophagy in melanoma cells. Transcriptomic data and real‐time PCR analysis demonstrated reduced expression of autophagy related 16 like 2 ( ATG16L2 ) in TRAF6‐deficient melanoma cells. ATG16L2 knockdown resulted in increased autophagy and apoptosis. Mechanism studies confirmed that TRAF6 regulated ATG16L2 expression through c‐Jun. Importantly, targeting TRAF6 with cinchonine, a TRAF6 inhibitor, effectively suppressed the growth of melanoma cells by inducing autophagy and apoptosis through the TRAF6/c‐Jun/ATG16L2 signaling pathway. These findings highlight the pivotal role of TRAF6 in regulating autophagy and apoptosis in melanoma, emphasizing its significance as a novel therapeutic target for melanoma treatment.